Porphyromonas gingivalis Outer Membrane Vesicles Induce Selective Tumor Necrosis Factor Tolerance in a Toll-Like Receptor 4- and mTOR-Dependent Manner

Waller, Tobias; Kesper, Laura; Hirschfeld, Josefine; Dommisch, Henrik; Kölpin, Johanna; Oldenburg, Johannes; Uebele, Julia; Hoerauf, Achim; Deschner, James; Jepsen, Søren; Bekeredjian‐Ding, Isabelle

doi:10.1128/iai.01390-15

Cited by 35 publications

(35 citation statements)

References 62 publications

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“…Treatment with mbcd prevented delivery of OmpA from A. baumannii OMVs to host cells (Jin et al, 2011). OMVs commonly cause immune activation via the induction of cytokines, and their production is measured using ELISAs to determine the level of inflammatory stimulation (Schaar et al, 2011;Sharpe et al, 2011;Elmi et al, 2012;Pollak et al, 2012;Kunsmann et al, 2015;Mondal et al, 2016;Waller et al, 2016). Treatment of host cells with mbcd prior to infection with OMVs from Campylobacter jejuni resulted in reduced production of IL-8, IL-6 and TNF-α (Elmi et al, 2012).…”

Section: Non Clathrin Mediated Endocytosismentioning

confidence: 99%

Mechanisms of outer membrane vesicle entry into host cells

O’Donoghue

Krachler

2016

Cellular Microbiology

245

214

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Bacterial outer membrane vesicles (OMVs) are nano‐sized compartments consisting of a lipid bilayer that encapsulates periplasm‐derived, luminal content. OMVs, which pinch off of Gram‐negative bacteria, are now recognized as a generalized secretion pathway which provides a means to transfer cargo to other bacterial cells as well as eukaryotic cells. Compared with other secretion systems, OMVs can transfer a chemically extremely diverse range of cargo, including small molecules, nucleic acids, proteins, and lipids to proximal cells. Although it is well recognized that OMVs can enter and release cargo inside host cells during infection, the mechanisms of host association and uptake are not well understood. This review highlights existing studies focusing on OMV‐host cell interactions and entry mechanisms, and how these entry routes affect cargo processing within the host. It further compares the wide range of methods currently used to dissect uptake mechanisms, and discusses potential sources of discrepancy regarding the mechanism of OMV uptake across different studies.

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Section: Non Clathrin Mediated Endocytosismentioning

confidence: 99%

Mechanisms of outer membrane vesicle entry into host cells

O’Donoghue

Krachler

2016

Cellular Microbiology

245

214

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“…Local immune evasion of P. gingivalis was accomplished by its outer membrane vesicles (OMVs) which promoted monocyte unresponsiveness to live P. gingivalis (55). Neutralization of IL-10 during OMV challenge partially restored monocyte responsiveness to P. gingivalis while full reactivity to this bacterium was regained by inhibiting the target of rapamycin (mTOR) intracellular signaling pathway which is the major signaling pathway for promoting TLR2-/TLR4-mediated tolerance in monocytes.…”

Section: T Cellsmentioning

confidence: 99%

Porphyromonas gingivalissuppresses adaptive immunity in periodontitis, atherosclerosis, and Alzheimer’s disease

Olsen

Taubman²,

Singhrao

2016

Journal of Oral Microbiology

112

102

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Porphyromonas gingivalis, a keystone pathogen in chronic periodontitis, has been found to associate with remote body organ inflammatory pathologies, including atherosclerosis and Alzheimer’s disease (AD). Although P. gingivalis has a plethora of virulence factors, much of its pathogenicity is surprisingly related to the overall immunosuppression of the host. This review focuses on P. gingivalis aiding suppression of the host’s adaptive immune system involving manipulation of cellular immunological responses, specifically T cells and B cells in periodontitis and related conditions. In periodontitis, this bacterium inhibits the synthesis of IL-2 and increases humoral responses. This reduces the inflammatory responses related to T- and B-cell activation, and subsequent IFN-γ secretion by a subset of T cells. The T cells further suppress upregulation of programmed cell death-1 (PD-1)-receptor on CD+cells and its ligand PD-L1 on CD11b+-subset of T cells. IL-2 downregulates genes regulated by immune response and induces a cytokine pattern in which the Th17 lineage is favored, thereby modulating the Th17/T-regulatory cell (Treg) imbalance. The suppression of IFN-γ-stimulated release of interferon-inducible protein-10 (IP-10) chemokine ligands [ITAC (CXCL11) and Mig (CXCL9)] by P. gingivalis capsular serotypes triggers distinct T cell responses and contributes to local immune evasion by release of its outer membrane vesicles. In atherosclerosis, P. gingivalis reduces Tregs, transforms growth factor beta-1 (TGFβ-1), and causes imbalance in the Th17 lineage of the Treg population. In AD, P. gingivalis may affect the blood–brain barrier permeability and inhibit local IFN-γ response by preventing entry of immune cells into the brain. The scarcity of adaptive immune cells in AD neuropathology implies P. gingivalis infection of the brain likely causing impaired clearance of insoluble amyloid and inducing immunosuppression. By the effective manipulation of the armory of adaptive immune suppression through a plethora of virulence factors, P. gingivalis may act as a keystone organism in periodontitis and in related systemic diseases and other remote body inflammatory pathologies.

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“…To further complicate the picture, there is evidence for immune evasion by pathogen-derived MVs as well as immune modulation by commensal-derived MVs (Vidakovics et al, 2010; Shen et al, 2012; Waller et al, 2016). Nonetheless, our current knowledge collectively suggests that (1) MVs are a central mechanism for intercellular communication between bacteria and host cells during infection, and (2) MV secretion can be beneficial to the host as well as the pathogen.…”

Section: Immune Modulation By Bacterial Membrane Vesiclesmentioning

confidence: 99%

Interspecies Communication between Pathogens and Immune Cells via Bacterial Membrane Vesicles

Jurkoshek

Wang

Athman

et al. 2016

Front. Cell Dev. Biol.

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The production of extracellular vesicles is a universal mechanism for intercellular communication that is conserved across kingdoms. Prokaryotes secrete 50–250 nm membrane vesicles (MVs) in a manner that is regulated by environmental stress and is thought to promote survival. Since many types of host-derived stress are encountered during infection, this implies an important role for MV secretion in bacterial pathogenesis. Accordingly, MVs produced by gram-positive and gram-negative pathogens contain toxins, virulence factors, and other molecules that promote survival in the host. However, recent studies have also shown that bacterial MVs are enriched for molecules that stimulate innate and adaptive immune responses. As an example, MVs may serve multiple, important roles in regulating the host response to Mycobacterium tuberculosis (Mtb), an intracellular pathogen that infects lung macrophages and resides within modified phagosomes. Previously, we demonstrated that Mtb secretes MVs during infection that may modulate infected and uninfected immune cells. Our present data demonstrates that Mtb MVs inhibit the functions of macrophages and T cells, but promote Major Histocompatibility Complex (MHC) class II antigen presentation by dendritic cells. We conclude that bacterial MVs serve dual and opposing roles in the activation of and defense against host immune responses to Mtb and other bacterial pathogens. We also propose that MV secretion is a central mechanism for interspecies communication between bacteria and host cells during infection.

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Porphyromonas gingivalis Outer Membrane Vesicles Induce Selective Tumor Necrosis Factor Tolerance in a Toll-Like Receptor 4- and mTOR-Dependent Manner

Cited by 35 publications

References 62 publications

Mechanisms of outer membrane vesicle entry into host cells

Mechanisms of outer membrane vesicle entry into host cells

Porphyromonas gingivalissuppresses adaptive immunity in periodontitis, atherosclerosis, and Alzheimer’s disease

Interspecies Communication between Pathogens and Immune Cells via Bacterial Membrane Vesicles

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